title: CGX-1007 prevents excitotoxic cell death via actions at multiple types of NMDA receptors.
abstract: Glutamate induced excitotoxic injury through over-activation of N-methyl-D-aspartate receptors (NMDARs) plays a critical role in the development of many neurodegenerative diseases. The present study was undertaken to evaluate the role of CGX-1007 (Conantokin G) as a neuroprotective agent against NMDA-induced excitotoxicity. Conantokin G, a cone snail peptide isolated from Conus geographus is reported to selectively inhibit NR2B containing NMDARs with high specificity and is shown to have potent anticonvulsant and antinociceptive effects. CGX-1007 significantly reduced the excitotoxic cell death induced by NMDA in organotypic hippocampal brain slice cultures in a concentration-dependent manner. In contrast, ifenprodil, another NR2B specific antagonist failed to offer neuroprotection against NMDA-induced excitotoxicity. We further determined that the neuroprotection observed is likely due to the action of CGX-1007 at multiple NMDA receptor subtypes. In a series of electrophysiology experiments, CGX-1007 inhibited NMDA-gated currents in human embryonic kidney (HEK) 293 cells expressing NMDA receptors containing either NR1a/NR2B or NR1a/NR2A subunit combinations. CGX-1007 produced a weak inhibition at NR1a/NR2C receptors, whereas it had no effect on NR1a/NR2D receptors. Further, the inhibition of NMDA receptors by CGX-1007 was voltage-dependent with greater inhibition seen at hyperpolarized membrane potentials. The voltage-dependence of CGX-1007 activity was also observed in recordings of NMDA-gated currents evoked in native receptors expressed in cortical neurons in culture. Based on our results, we conclude that CGX-1007 is a potent neuroprotective agent that acts as an antagonist at both NR2A and NR2B containing receptors.
authors.affiliation: Department of Pharmacology & Toxicology,Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Salt Lake City, UT 84108, USA.
authors.forename: Anitha B
authors.initials: AB
authors.lastname: Alex
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Saunders
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dalpé-Charron
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D020916:Conotoxins / Q000494:pharmacology*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection
chemical_list: D020916:Conotoxins; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C473649:NR1A NMDA receptor, rat; C121001:NR2B NMDA receptor; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; C055407:conotoxin GV